ABSTRACT Nicotine is a highly addictive substance, and cigarette smoking is a major cause of premature death among humans. Little is known about the neuropharmacology and sites of action of nicotine in the human brain. Such knowledge might help in the development of new behavioral and pharmacological therapies to aid in treating nicotine dependence and to improve smoking cessation success rates.
Functional magnetic resonance imaging, a real-time imaging technique, was used to determine the acute CNS effects of intravenous nicotine in 16 active cigarette smokers. An injection of saline followed by injections of three doses of nicotine (0.75, 1.50, and 2.25 mg/70 kg of weight) were each administered intravenously over 1-minute periods in an ascending, cumulative-dosing paradigm while whole brain gradient-echo, echo-planar images were acquired every 6 seconds during consecutive 20-minute trials.
Nicotine induced a dose-dependent increase in several behavioral parameters, including feelings of "rush" and "high" and drug liking. Nicotine also induced a dose-dependent increase in neuronal activity in a distributed system of brain regions, including the nucleus accumbens, amygdala, cingulate, and frontal lobes. Activation in these structures is consistent with nicotine's behavior-arousing and behavior-reinforcing properties in humans.
The identified brain regions have been previously shown to participate in the reinforcing, mood-elevating, and cognitive properties of other abused drugs such as cocaine, amphetamine, and opiates, suggesting that nicotine acts similarly in the human brain to produce its reinforcing and dependence properties.

[Show abstract][Hide abstract]ABSTRACT:
Aims and Methods: Acute alcohol administration induces marked decreases in glucose metabolism throughout the human brain. However, the relationship between alcohol’s effects on brain metabolism and the behavioural changes that occur with intoxication are still unclear. Here we assessed this association using principal component analysis for dimension reduction and canonical correlations to gauge inter-class relationships. We also used canonical correlations in the polynomial space to assess for possible nonlinear relationships. Results: After normalizing the regional measures to account for the large whole brain decreases observed with intoxication we show that the largest decreases occurred in occipital cortex and that there were relative increases in basal ganglia. Principal component analysis of the changes in the normalized measures revealed that 60% of the variance was accounted for by two factors; one that contrasted cerebellum versus frontal and anterior cingulate metabolism, and another that contrasted basal ganglia and insula. The square of the first factor was significantly correlated with the deterioration in cognitive performance. The second factor showed a significant linear correlation with self-reports of intoxication and with deterioration in cognitive and motor performance. Conclusions: These findings suggest that the contrasting effects of alcohol in basal ganglia versus the insula are involved in the perception of ‘feeling drunk’ and that its contrasting effects in cerebellum versus those in frontal and parietal cortices are involved in its motor incoordinating effects. On the other hand alcohol’s impact on cognitive performance implicates a more complex pattern of brain effects that includes linear as well as non-linear associations.

[Show abstract][Hide abstract]ABSTRACT:
Obesity presents a major health hazard of the 21st century. It promotes co-morbid diseases such as heart disease, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis. Excessive energy intake, physical inactivity, and genetic susceptibility are main causal factors for obesity, while gene mutations, endocrine disorders, medication, or psychiatric illnesses may be underlying causes in some cases. The development and maintenance of obesity may involve central pathophysiological mechanisms such as impaired brain circuit regulation and neuroendocrine hormone dysfunction. Dieting and physical exercise offer the mainstays of obesity treatment, and anti-obesity drugs may be taken in conjunction to reduce appetite or fat absorption. Bariatric surgeries may be performed in overtly obese patients to lessen stomach volume and nutrient absorption, and induce faster satiety. This review provides a summary of literature on the pathophysiological studies of obesity and discusses relevant therapeutic strategies for managing obesity.

Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed.
The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual
current impact factor.
Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence
agreement may be applicable.

Page 1

Am J Psychiatry 155:8, August 1998Regular ArticlesSTEIN, PANKIEWICZ, HARSCH, ET AL.NICOTINE-INDUCED LIMBIC CORTICAL ACTIVATIONNicotine-Induced Limbic Cortical Activationin the Human Brain: A Functional MRI StudyElliot A. Stein, Ph.D., John Pankiewicz, M.D., Harold H. Harsch, M.D.,Jung-Ki Cho, M.D., Scott A. Fuller, B.S., Raymond G. Hoffmann, Ph.D.,Marjorie Hawkins, M.D., Stephen M. Rao, Ph.D., Peter A. Bandettini, Ph.D.,and Alan S. Bloom, Ph.D.Objective: Nicotine is a highly addictive substance, and cigarette smoking is a majorcause of premature death among humans. Little is known about the neuropharmacologyand sites of action of nicotine in the human brain. Such knowledge might help in the devel-opment of new behavioral and pharmacological therapies to aid in treating nicotine depen-dence and to improve smoking cessation success rates. Method: Functional magnetic reso-nance imaging, a real-time imaging technique, was used to determine the acute CNS effectsof intravenous nicotine in 16 active cigarette smokers. An injection of saline followed byinjections of three doses of nicotine (0.75, 1.50, and 2.25 mg/70 kg of weight) were eachadministered intravenously over 1-minute periods in an ascending, cumulative-dosing para-digm while whole brain gradient-echo, echo-planar images were acquired every 6 secondsduring consecutive 20-minute trials. Results: Nicotine induced a dose-dependent increasein several behavioral parameters, including feelings of “rush” and “high” and drug liking.Nicotine also induced a dose-dependent increase in neuronal activity in a distributed systemof brain regions, including the nucleus accumbens, amygdala, cingulate, and frontal lobes.Activation in these structures is consistent with nicotine’s behavior-arousing and behavior-reinforcing properties in humans. Conclusions: The identified brain regions have beenpreviously shown to participate in the reinforcing, mood-elevating, and cognitive propertiesof other abused drugs such as cocaine, amphetamine, and opiates, suggesting that nicotineacts similarly in the human brain to produce its reinforcing and dependence properties. (Am J Psychiatry 1998; 155:1009–1015)Tof death in the United States (1). It meets all of theDSM-IV criteria for drug dependence, including com-obacco dependence is the most common substanceabuse disorder and the leading preventable causepulsive use, difficulty in quitting, and withdrawalsymptoms upon cessation of chronic use. Only about3% of smokers who try to quit remain abstinent for 1year (2). Although there are more than 2,000 com-pounds in cigarette smoke, nicotine alone has beenshown to produce tolerance, dependence, and a distinctwithdrawal syndrome in both animals and humans (3).It is generally considered to be the addictive and rein-forcing agent responsible for continued smoking behav-ior (1, 4, 5), and while the mechanisms underlying itsreinforcing properties are not well understood, nicotineis thought to interact with the mesocorticolimbic dopa-mine system in a manner similar to that of other abuseddrugs such as cocaine (3, 6, 7).Nicotine produces profound behavioral effects in hu-Data presented in part at the College on Problems of Drug De-pendence, Scottsdale, Ariz., June 10–15, 1995. Received Sept. 22,1997; revision received March 23, 1998; accepted April 3, 1998.From the Departments of Psychiatry, Pharmacology, Neurology,and Biostatistics and the Biophysics Research Institute, Medical Col-lege of Wisconsin. Address reprint requests to Dr. Stein, Departmentof Psychiatry, Medical College of Wisconsin, 8701 Watertown PlankRd., Milwaukee, WI 53226; estein@mcw.edu (e-mail). Supported in part by grant DA-09465 from the National Instituteon Drug Abuse to Dr. Stein and NIH General Clinical Research Cen-ter grant RR-00058.Am J Psychiatry 155:8, August 19981009

Page 2

mans, including memory facilitation, locomotor activa-tion, mild anti-nociception, calming, and appetite sup-pression (8). However, little is known of nicotine’s ef-fects on neuronal activity at a systems level in animals(9–11), and almost nothing is known about this in hu-mans. Understanding the sites and mechanisms of nico-tine’s action in the human brain, along with our knowl-edge of its behavioral pharmacology and its potentialaddictive properties in common with those of otherabused substances, may lead to new concepts related tothe central mechanisms of drug dependence and the de-velopment of novel smoking cessation therapies.Functional magnetic resonance imaging (MRI) al-lows for the noninvasive study of human brain activityby measuring localized, intrinsic signal changes that aredirectly driven by changes in neuronal activity. Becauseof its excellent temporal and spatial resolution, we usedthis imaging tool to identify neuroanatomical regionsactivated by nicotine in the human brain. We hypothe-sized that frontal lobe and limbic/cingulate corticalstructures would be activated by nicotine, consistentwith the drug’s mood-altering, attentional, and vigi-lance properties. Further, since nicotine is a stimulantand addictive agent, we hypothesized that regions pre-viously implicated in animal models of drug abuse, suchas the nucleus accumbens, would also be activated inhumans after nicotine administration.METHODSubjects were recruited through newspaper advertisements. Theywere generally healthy individuals (nine male and seven female) be-tween the ages of 18 and 39 years (mean=25.9, SD=6.0) with smokinghistories averaging 8.5 years (SD=5.4, range=1.5–23) and current useof about one pack of cigarettes per day. All but two subjects werestrongly right-handed according to the Edinburgh Handedness Inven-tory (12). The subjects had no previous history of any neurological orpsychiatric disorder and no other drug dependence. The experimentswere approved by the institutional review board of the Medical Col-lege of Wisconsin. Brief physical and history examinations were con-ducted before the initiation of any experimental procedure. Aftercomplete description of the study to the subjects, written informedconsent was obtained. Subjects were instructed that they shouldsmoke as they wished during all phases of their participation in thestudy. Their only restriction was no alcohol consumption for 24hours and no caffeine consumption for 12 hours before scanning.To determine safety and obtain physiological and behavioral meas-ures, before their scanning session the subjects received an intrave-nous injection of saline into an antecubital vein, followed by threeinjections of nicotine (0.75, 1.50, and 2.25 mg/70 kg of body weight).All injections lasted for 1 minute and occurred in ascending dose or-der every 20–30 minutes while the subjects were recumbent in bed atthe Medical College of Wisconsin General Clinical Research Center.Subjects were continuously monitored for blood pressure and pulserate and by ECG and were asked to respond on 10-point Likert scalesat 2, 5, and 15 minutes after injection to eight behavioral rating ques-tions (feelings of “rush,” “high,” pleasantness, anxiety, confusion,and sedation, intensity of drug effect, and drug liking). A second in-travenous catheter was used to collect blood samples for determina-tion of serum nicotine concentrations by gas chromatography-massspectrometry (13).Approximately 1 week later, the same three doses of nicotine wereadministered while the subjects underwent functional MRI scanning.The subjects reported to the MRI facility approximately 30 minutesbefore their scan appointment. All of them reported smoking a ciga-rette immediately before entering the hospital. Scan sessions, approxi-mately 2 hours in duration, began between 8:00 p.m. and 1:00 a.m.Whole brain functional MRI data were acquired with a 1.5-T Signascanner (GE Medical Systems, Milwaukee) equipped with a 30.5-cminternal diameter three-axis, balanced-torque local gradient coil de-signed specifically for rapid gradient switching and a shielded-quad-rature elliptical encapped transmit/receive birdcage radio frequencycoil inserted inside the gradient coil (14). Eight contiguous 8-mm ax-ial slices were acquired with use of a blipped, gradient-echo, echo-pla-nar image pulse sequence (TE=40 msec) with an interscan resolutionof 6 seconds during the 20-minute acquisition period and a 24-cmfield of view with an in-plane resolution of 3.75 mm. During each20-minute scan, the first 4 minutes consisted of baseline data acqui-sition, followed by the 1-minute intravenous injection, and then 15minutes of postdrug data acquisition. The blood-oxygen-level-depen-dent pulse sequence we used is weighted to be most sensitive tochanges in blood oxygenation levels rather than blood flow altera-tions. Anatomical images (spoiled gradient/recall acquisition in thesteady state [GRASS], 256×256 pixels, 1.1 mm thick) were acquiredimmediately before functional MRI data acquisition.Functional MRI data were analyzed with an algorithm and associ-ated software that we developed, which is based on the working hy-pothesis that parenchyma-derived signals should follow a pharma-cokinetic model; that is, the arterial drug concentration curve isposited to reflect the brain drug concentration distribution, which inturn drives brain activation patterns (A.S. Bloom et al., manuscriptsubmitted for publication). Active voxels were detected according tosix criteria: time to peak effect (1–8 minutes after the start of theinjection), magnitude and statistical significance of the peak effect(≥0.5% over baseline and p≤10–6, unpaired t test), slope of the risingphase of the response curve (0.5–5.0), time to decline back to 50% ofthe peak effect (4–12 minutes after injection), and baseline periodstability (≤11% of the mean range for all voxels in the brain). Theacceptable range given in parentheses for each parameter was deter-mined from the known pharmacokinetics of nicotine, the observedvenous blood levels, and the physiological and behavioral effects seenin this study. To be considered active, a voxel had to meet all of thesix criteria. Functional images were generated by applying the algo-rithm to each pixel and overlaying activated regions on high-resolu-tion, three-dimensional spoiled GRASS images. Nearest-neighborpixel analysis was performed to preclude isolated pixel recognition.All data were transformed into the stereotaxic coordinate system ofFIGURE 1. Mean Serum Nicotine Concentrations, as Deter-mined by Gas Chromatography-Mass Spectrometry, of 16 Sub-jects After Three Different Intravenous Doses of NicotineaaAnalysis of variance indicated a significant effect of time (F=4.11,df=2, 46, p≤0.02) and dose (F=4.50, df=2, 46, p≤0.02). There wasno time-by-dose interaction, indicating that the serum half-livesamong the doses were not significantly different.NICOTINE-INDUCED LIMBIC CORTICAL ACTIVATION1010Am J Psychiatry 155:8, August 1998

Page 3

Talairach and Tournoux (15), averaged across all subjects at eachdose to produce mean dose-response activation maps, and displayedwith the use of AFNI (16). To compensate for the anatomical uncer-tainty of the Talairach and Tournoux transformation, a 3-mm blurwas formed around activated pixels.Statistical significance for the combined group data was deter-mined on the basis of a probability function derived from a beta bi-nomial distribution of each individual’s response after the saline in-jection. A centers-of-mass analysis was used to determine regions ofinterest, with a minimum volume of tissue set at 150 ml. Clustersbelow this size were ignored in further analysis. The intensity of allpixels within the cluster was set at the maximum intensity within thecluster. Across all subjects, after the saline injection, less than 3% ofthe voxels in the brain met the strict criteria for activation outlinedabove. Further, in the group mean activation maps, no clusters of 150ml or greater were found after the saline injection, indicating a verylow probability of a false positive with use of this waveform analysismethod.RESULTSWhen measured 2 minutes after administration, nico-tine had no significant effect on heart rate or bloodpressure. Mean arterial pressure increased only tran-siently for 10–20 seconds, from a baseline of about 91mm Hg to a mean peak of about 99.5 mm Hg. Never-theless, after the nicotine injections the subjects re-ported experiencing moderate “rush” and “high” feel-ings that were dose- and time-dependent (mean peakrush scores=2.5, 4.6, and 5.7 out of a possible 10 afterthe low, medium, and high doses, respectively). Boththe rush and the high peaked at 2 minutes after injectionand returned to baseline by 5 minutes after. In contrast,scores on pleasantness averaged about 5 at all doses andpersisted for 15 minutes. Finally, the participants re-ported moderately liking the experience (mean peak re-sponse rating=4.1, SD=2.1), with no significant effecton feelings of sedation, confusion, or anxiety. Plasmanicotine levels (figure 1) accurately approximated boththe behavioral and functional MRI signal time courses.Dose-dependent increases in plasma levels reachedmaximum values at 2 minutes and rapidly decreased toabout two-thirds of peak value within 15 minutes.Baseline nicotine levels were virtually undetectable atless than 10 ng/ml. No prolonged untoward effectswere ever reported; all subjects agreed to receive allFIGURE 2. Functional MRI Time Course Data on a Single Subject After Intravenous Injection of 1.50 mg of NicotineaaSuperimposed on the T1-weighted, fast spin echo-planar image(EPI) is a map of all nicotine-activated voxels (red boxes) from thatbrain slice (left side). The box outlined in blue denotes the 3×3 voxelregion of interest corresponding to the time course data shown onthe right side of the figure. The nine independent time coursegraphs (right side) illustrate the functional MRI signal plotted againsttime and are derived from the nine contiguous voxels depicted inthe posterior cingulate. The arrow indicates the onset time of the1-minute injection. Note the rapid rise in signal in three of the voxelsand its exponential time decay, with the signal returning to baselinewithin 15 minutes. These three voxels, plus the smaller effect seenin the upper right voxel, were among those that both met the criteriaof the waveform recognition algorithm and were indicated within theregion-of-interest box. Note also the heterogeneous nature of theresponse, with adjacent 3.75-mm voxels showing no apparent drugeffect.STEIN, PANKIEWICZ, HARSCH, ET AL.Am J Psychiatry 155:8, August 19981011

Page 4

nicotine doses, and all returned for subsequent func-tional MRI scanning.Regional brain functional MRI signal intensity rap-idly increased from baseline levels after nicotine ad-ministration, reached a peak response approximately2.8 minutes after the end of the 1-minute intravenousinjection, and returned to one-half of the maximumlevel approximately 5.6 minutes after drug administra-tion (figure 2). While this response pattern was not theonly one seen, it was by far the most dominant and theone used to extract drug-induced localized brain activa-tion from the functional MRI signal. When averagedacross all participants, neither percent signal change,time to peak effect, nor time to one-half the maximumeffect changed significantly as a function of dose. Incontrast, the percentage of voxels activated increasedfrom 3.38% after saline to 7.06% , 11.06% , and10.90% after the low, medium, and high nicotinedoses, respectively (F=14.35, df=3, 45, p<0.0001). Thenumbers of activated voxels were greater after both themedium and high doses of nicotine compared to saline,and the medium dose effect was also greater than thelow dose effect (Scheffé F test, p≤0.05).Significant regional activation (table 1) was seen inthe insula, anterior and posterior cingulate, frontallobes (orbital, dorsolateral, and medial frontal), andportions of the temporal and visual occipital cortex.While some visual and frontal regions were activatedonly after low nicotine doses, perhaps demonstratingrapid response tolerance in these areas to the cumula-tive dosing paradigm we used, other regions (includingtemporal, visual, and parietal lobes) became activatedonly after the higher doses, suggesting a higher thresh-old for effect in these regions. Finally, a number of lim-bic subcortical regions were activated (figure 3), includ-ing the nucleus accumbens, amygdala, hypothalamus,and several nuclei within the limbic thalamus (e.g.,mediodorsal, anterior, and lateroposterior nuclei).DISCUSSIONIn this study, intravenous nicotine strongly activateda distributed system of CNS regions implicated in thecontrol and regulation of many of the behavioral stateslong attributed to nicotine use. The cingulate and sev-eral frontal lobe divisions, including the dorsolateral,orbital, and medial frontal, were among the mostprominently activated regions. The frontal lobes—withtheir rich dopamine innervation—and the cingulatecortex—through its connections with many neocorticalassociation, motor, and sensory regions—have beenthought to be involved in the processing of such diversecognitive states as working memory, attention, motiva-tion, mood, and emotion (17, 18). All of these areknown to be modified by nicotine intake (19). In addi-tion, nicotinic receptors are present on both the soma-todendritic and axon terminals of locus ceruleus norad-renergic neurons (20), which are known to project tomuch of the forebrain and hippocampus. These locusceruleus neurons and their projections are thought toregulate or modulate behavioral arousal and vigilance(21). Taken together with what is known of brain re-gional structure-function relationships, the functionalMRI brain activation pattern in this study is consistentwith recurrent reports by cigarette smokers that smok-ing enhances—whereas smoking abstinence and with-drawal compromise—arousal, mood, vigilance, and at-tention, among other cognitive processes (19).Although cigarette smoking has been reported tomodify numerous cognitive behaviors, including atten-tion and working memory (8, 19), nicotine’s behavioralproperties in humans have been difficult to attribute tospecific brain regions because of the sometimes subtleand diffuse nature of the drug’s effect and the rapidTABLE 1. Dose-Response Effects of Intravenous Nicotine In-jections on Regional Functional MRI Signals in 16 SubjectsaSide ActivatedBrain AreaAfter0.75-mgDoseAfter1.50-mgDoseAfter2.25-mgDoseCortexPosterior orbital gyrusLateral orbital gyrusCingulate cortexInferior frontal gyrusMedial frontal gyrusSuperior frontal gyrusPrecentral gyrusInferior temporal gyrusMedial temporal gyrusSuperior temporal gyrusInsular cortex (posterior)Insular cortex (anterior)Postcentral gyrusSuperior parietal cortexLingual gyrusAngular gyrusCuneusPrecuneusMedial occipital gyrusInferior occipital gyrusLateral occipital gyrusSupramarginal gyrusAmygdalaDiencephalonPulvinarVentral anteriorMedial dorsal nucleusDorsal lateral nucleusPosterior lateral nucleusAnterior nucleusVentral lateral nucleusHypothalamusBasal gangliaPutamenCaudate nucleusNucleus accumbensGlobus pallidusSuperior colliculusInferior colliculusRightRightBothBothBothLeftBothLeftRightBothLeftBothRightRightBothBothBothBothBothBothBothBothLeftLeftBothLeftLeftLeftLeftRightLeftLeftBothRightBothBothLeftLeftBothBothBothBothBothBothLeftLeftBothBothLeftRightLeftLeftRightLeftBothBothLeftRightRightLeftRightLeft BothBothLeftRightBothLeftRightRightRightLeftLeftaGroup data represent the areas that both met the criteria of thewaveform recognition algorithm and were significantly differentfrom data obtained after an individual’s matched saline injection(p≤0.001, beta distribution).NICOTINE-INDUCED LIMBIC CORTICAL ACTIVATION1012Am J Psychiatry 155:8, August 1998

Page 5

smoking-withdrawal cyclesthat make “baseline” behav-ioral levels difficult to de-fine. This observation mayhelp explain why the cogni-tion-enhancing propertiesof nicotine have been mostconvincingly demonstratedin acutely abstinent smok-ers. It has been more diffi-cult to demonstrate theseproperties in nonabstinentsmokers and in nonsmokers(22), suggesting that someof the reported behavioraleffects may reflect with-drawal relief. It has not beendemonstrated whether nico-tine replacement acts in a“ nonspecific” fashion toameliorate withdrawal-in-duced dysthymia (allevia-tion of which might bemanifested as a positive ef-fect on cognition) or acts di-rectly on CNS structuresprimarily involved in cogni-tive systems. However, inview of the brain regions ac-tivated in this study, ourdata support the hypothesisthat direct activation of thefrontal and cingulate re-gions by nicotine is respon-sible for the drug’s primarybehavioral and mood-alter-ing effects.Although cigarettes gener-ally produce only a moderate euphorigenic state, hu-man cocaine abusers often identify the effects of in-travenous nicotine as similar to and, in many cases,identical to those of intravenous cocaine (4). This ob-servation suggests that the reinforcing and drug-dis-criminative properties of both drugs probably sharecommon anatomical sites and mechanisms throughtheir ability to ultimately enhance mesocorticolimbicdopamine transmission, albeit through different cel-lular mechanisms. In this study, among the regionsthat nicotine activated were the nucleus accumbens,amygdala, limbic thalamus, and frontal lobe cortical re-gions that have consistently been implicated in the re-inforcing properties of both nicotine and cocaine in ani-mal experiments (4, 23–25), suggesting the two drugs’common mechanisms in humans as well. Indeed, theonly brain area in the rat that supports direct cocaineself-administration is the medial prefrontal cortex (26),the human homologue of which includes the mediodor-sal thalamus terminal fields of the orbitofrontal andmedial frontal lobes (27)—regions activated by nicotinein the present study.To our knowledge, there have been no previouslypublished human studies that have used functionalMRI to examine regional patterns of neuronal activityafter acute nicotine administration. In two preliminaryreports (each with three subjects) (28, 29), Nagata et al.(28) reported increased cerebellar and frontal lobeblood flow after cigarette smoking in a study that used15O positron emission tomography (PET), while Lon-don (29) reported a generalized decrease in glucose up-take after 1.5 mg i.v. of nicotine. Another previous in-dication of the central sites of nicotine action in thehuman brain came from the distribution of nicotine-binding sites noted with PET (30). Although receptorbinding does not necessarily indicate primary site of ac-tion, the present functional activation data agree re-markably well with these human receptor maps. Thelargest concentrations of [11C]nicotine binding sites areseen in the frontal, cingulate, and insular lobes of thecortex and in the thalamus and basal ganglia. In addi-tion to our observation of significant functional MRIactivity in all of these regions, a notable finding fromthe present study is the significant activation of the vis-FIGURE 3. Composite Functional MRI Images After Intravenous Injection of 2.25 mg of Nico-tine, Averaged Across 16 Subjects, With Individual Brains Normalized Into Talairach Spaceaa(See atlas of Talairach and Tournoux [15]). Areas that met the criteria of the waveform recognitionalgorithm and were significantly different from saline (p≤0.001, beta distribution) are indicated in colorand superimposed on a single subject’s spoiled GRASS anatomical data set. The red-to-yellow colormap depicts percent signal change above baseline. Note the relatively constant magnitude of effectacross the areas affected by nicotine. Blue crosshairs in part I illustrate equivalent locations in thecoronal, sagittal, and axial sections, respectively. Note in the coronal section (part I, left) arrowspointing to the cingulate and lateral orbital gyrus. Additional major areas of activation illustratedinclude the superior, middle, and inferior frontal gyri. In addition to the indicated lateral orbital gyrus,the axial view (part I, center) illustrates major activation in the insula, colliculus, medial geniculate,hypothalamus, putamen, and globus pallidus, and the sagittal view (part I, right) shows major acti-vation in the insula and transverse temporal gyrus. Notable subcortical limbic regions activated areillustrated in part II and include the nucleus accumbens, amygdala, and thalamus.STEIN, PANKIEWICZ, HARSCH, ET AL.Am J Psychiatry 155:8, August 19981013

Page 6

ual cortex. This activation may have been the result ofprimary nicotinic receptor binding in subcortical visualrelay nuclei (e.g., the lateral geniculate) that are knownto have high nicotinic receptor concentrations (31, 32)or presynaptic nicotinic binding in the cortex. Nicotinicreceptors have also been reported in many thalamic nu-clei in rats (33). These nuclei project, in turn, to thetemporal lobe auditory and visual occipital cortex andwidespread regions of the frontal, cingulate, and parie-tal cortex. Thus, some of the most activated corticalregions after administration of intravenous nicotine inthis study may reflect intense subcortical, thalamicnicotinic receptor activation.The observation of unilateral regional activation fol-lowing drug administration was unexpected and deservesmention. Several recent human metabolic mapping stud-ies have reported right dominant activation after admini-stration of cocaine (34) and marijuana (35). While mostof the activation sites reported in table 1 were bilateral,many cortical and subcortical sites were activated onlyunilaterally. Left-right differences in drug effects shouldbe evaluated more closely, since they relate to changes indrug-induced behavioral states.It is unlikely that the changes in functional MRI sig-nal which we observed were the result of peripheral orcentral cardiovascular effects. Although nicotine canproduce changes in heart rate and blood pressure (3),which by themselves can indirectly alter global cerebralblood flow, no significant cardiovascular changes wereseen in the present experiment, which involved well-experienced, nicotine-tolerant subjects. Cerebral bloodflow may also be influenced by changes in respiratory-dependent PCO2 following nicotinic ganglionic activa-tion. However, such peripheral modulation wouldlikely produce homogeneous alterations in blood flowand blood-oxygen-level-dependent signal rather thanthe more distributed, heterogeneous pattern of activa-tion we observed. In addition, the blood-oxygen-level-dependent weighted pulse sequence and long interscantime used in this study are heavily weighted to reflectchanges in local oxygenation more than blood flow(36). Changes in regional brain metabolism (oxygen ex-traction and glucose utilization) are more uniquelylinked to neuronal activity than changes in cerebralblood flow, which may potentially reflect more gener-alized vascular alterations independent of regionalbrain activity, as in CO2-induced vasodilation (37).Taken together, these data suggest that the observedfunctional MRI signal changes reflect alterations inneuronal activity secondary to CNS nicotinic receptoractivation. The data from this study are the first to de-scribe the CNS regions acted upon by acute nicotineadministration in humans, are neuroanatomically con-sistent with the mood-elevating and anxiolytic effectsoften ascribed to cigarette smoking (19), and supportour hypothesis that the observed cortical activation un-derlies many of the behavioral properties of the drug.By revealing the regional activation and, importantly,the time course of nicotine’s action in the human brain(a feature that functional MRI is uniquely qualified toexamine), these data support the role of nicotine in thebehavioral effects observed during cigarette smoking.Notably, the real-time functional MRI signal in thisstudy peaked at approximately 2.8 minutes after drugadministration and is consistent with the peak plasmanicotine concentration observed at approximately 2minutes and the reported peak behavioral effects.Finally, it should be noted that other nicotine-inducedfunctional MRI waveforms were also occasionally ob-served but not analyzed for this report. For example,some waveforms increased at an appropriate postinjec-tion time but did not return to baseline during the apriori allotted time window for analysis. Whether thisresponse pattern reflects a neuronally induced, alterna-tive drug effect (e.g., prolonged activation) is currentlyunder investigation. For example, it might be positedthat multiple brain timing circuits are engaged by ciga-rette smoking, leading to behaviors with different timeconstants, i.e., variable interpuff intervals (in tens ofseconds) and intercigarette intervals (tens to hundredsof minutes). Only real-time measurements such as func-tional MRI have the potential to identify brain regionsresponsible for distinct portions of this complex behav-ior. It may now be possible to separate the CNS sitesresponsible for nicotine’s reinforcing properties fromthe drug’s other pharmacological effects. This wouldpermit testing hypotheses about the commonality ofmechanisms in abused drugs as well as serve as a pow-erful “bioassay” in the development of agents to man-age and treat nicotine abuse.REFERENCES 1. Jaffe J: Tobacco smoking and nicotine dependence, in NicotinePsychopharmacology: Molecular, Cellular and Behavioral As-pects. Edited by Wonnacott S, Russell MAH, Stolerman IP.New York, Oxford Press, 1990, pp 1–37 2. Centers for Disease Control: Smoking cessation during the pre-vious year among adults—United States, 1990 and 1991.MMWR Morb Mortal Wkly Rep 1993; 42:504–507 3. Henningfield JE, Miyasato K, Jasinski DR: Abuse liability andpharmacodynamic characteristics of intravenous and inhalednicotine. J Pharmacol Exp Ther 1985; 234:1–12 4. Henningfield JE, Miyasato K, Jasinski DR: Cigarette smokersself-administer intravenous nicotine. Pharmacol Biochem Be-hav 1983; 19:887–890 5. Stolerman IP, Jarvis MJ: The scientific case that nicotine is ad-dictive. Psychopharmacology (Berl) 1995; 117:2–10 6. Corrigall WA, Franklin KBJ, Coen KM, Clarke PBS: The meso-limbic dopaminergic system is implicated in the reinforcing ef-fects of nicotine. Psychopharmacology (Berl) 1992; 107:285–289 7. Corrigall WA, Coen KM: Selective dopamine antagonists re-duce nicotine self-administration. Psychopharmacology (Berl)1991; 104:171–176 8. Aceto MD, Martin BM: Central actions of nicotine. Med Res Rev1982; 2:43–62 9. London ED, Connolly RJ, Szikszay M, Wamsley JK, Dam M:Effects of nicotine on local cerebral glucose utilization in the rat.J Neurosci 1988; 8:3920–392810. Clarke PBS, Pert A: Autoradiographic evidence for nicotine re-ceptors on nigrostriatal and mesolimbic dopaminergic neurons.Brain Res 1985; 348:355–35811. Grunwald F, Schrock H, Kuschinsky W: The influence of nico-tine on local cerebral blood flow in rats. Neurosci Lett 1991;124:108–110NICOTINE-INDUCED LIMBIC CORTICAL ACTIVATION1014 Am J Psychiatry 155:8, August 1998